Abstract: The onset of Alzheimer's disease (AD) increases in incidence with age, and an increasing aging demographic means the number of individuals suffering from AD is expanding rapidly. Changes in cerebral metabolism are hallmarks of aging therefore it is reasonable to hypothesize that age-associated change in metabolism play major roles in AD progression. AD brains show clear metabolic impairments, and studies suggest that altered metabolism drives a cascade of events leading to AD onset. The mechanisms initiating these metabolic impairments remain a critical knowledge gap in AD research. We recently discovered that aberrant glycogen aggregates (AD-glycogen) are a universal feature of AD in both human and mice. Increases in AD-glycogen correlated with higher Braak staging and lower glucose levels in patient specimens. AD-glycogen is both hyper-phosphorylated and hyper-branched making them architecturally distinct from normal glycogen. We present strong evidence showing that AD-glycogen modulate brain metabolism through direct binding and inactivation of the AMP-activated protein kinase (AMPK), a master regulator of central carbon metabolism. We will first elucidate the molecular events leading to abnormal AD-glycogen formation in vitro and in vivo (Aim 1), then we will interrogate the impact of AD-glycogen on cerebral metabolism during aging (Aim 2). Finally, we will assess the efficacy of a novel glycogen-clearing enzyme therapy on brain metabolism, cognition, and AD neuropathology in vivo (Aim 3). The PI has assembled a multi-disciplinary team of investigators with complementary skillsets and state-of-art, high resolution, and Omic-based techniques to discover potential therapeutic options and possibly treat the onset of AD.